Substituted pyrazine-3-one-derivatives as IAP inhibitors

ABSTRACT

The present invention relates to novel IAP inhibitor compounds of formula I:

This application is a U.S. National Phase filing of InternationalApplication Serial No. PCT/US2007/025096 filed 7 Dec. 2007 and claimspriority to U.S. Provisional Application Ser. No. 60/873,436 filed 7Dec. 2006, the contents of which are incorporated herein by reference intheir entirety.

SUMMARY

The present invention relates generally to novel compounds that inhibitthe binding of the Smac protein to Inhibitor of Apoptosis Proteins(IAPs). The present invention includes novel compounds, novelcompositions, methods of their use and methods of their manufacture,wherein such compounds are generally pharmacologically useful as agentsin therapies whose mechanism of action rely on the inhibition of theIAP/caspase9 or Smac/IAP interaction, and more particularly useful intherapies for the treatment of proliferative diseases, including cancer.

BACKGROUND

Programmed cell death plays a critical role in regulating cell numberand in eliminating stressed or damaged cells from normal tissues.Indeed, the network of apoptotic signaling mechanisms inherent in mostcell types provides a major barrier to the development and progressionof human cancer. Since most commonly used radiation and chemotherapiesrely on activation of apoptotic pathways to kill cancer cells, tumorcells which are capable of evading programmed cell death often becomeresistant to treatment.

Apoptosis signaling networks are classified as either extrinsic whenmediated by death receptor-ligand interactions or intrinsic whenmediated by cellular stress and mitochondrial permeabilization. Bothpathways ultimately converge on individual Caspases. Once activated,Caspases cleave a number of cell death-related substrates, effectingdestruction of the cell.

Tumor cells have devised a number of strategies to circumvent apoptosis.One recently reported molecular mechanism involves the over expressionof members of the IAP family. IAPs sabotage apoptosis by directlyinteracting with and neutralizing Caspases. The prototype IAPs, XIAP andcIAP have three functional domains referred to as BIR 1, 2 & 3 domains.BIR3 domain interacts directly with Caspase 9 and inhibits its abilityto bind and cleave its natural substrate, Procaspase 3.

It has been reported that a proapoptotic mitochondrial protein, Smac(also known as DIABLO), is capable of neutralizing XIAP and/or cIAP bybinding to a peptide binding pocket (Smac binding site) on the surfaceof BIR3 thereby precluding interaction between XIAP and/or cIAP andCaspase 9. Binding of peptides derived from Smac has also been reportedto trigger autocatalytic polyubiquitination and subsequentproteosome-mediated degradation of CIAP1. The present invention relatesto therapeutic molecules that bind to the Smac binding pocket therebypromoting Caspase activation. Such therapeutic molecules are useful forthe treatment of proliferative diseases, including cancer.

SUMMARY OF THE INVENTION

The present invention relates generally to novel compounds that mimicthe binding of the Smac protein to Inhibitor of Apoptosis Proteins(IAPs). The present invention includes novel compounds, novelcompositions, methods of their use and methods of their manufacture,where such compounds are generally pharmacologically useful as agents intherapies whose mechanism of action rely on the inhibition of theIAP/Caspase9 or Smac/IAP interaction, and more particularly useful intherapies for the treatment of proliferative diseases, including cancer.

The present invention relates to compounds of the formula (I):

and pharmaceutically acceptable salts thereof, wherein

R₁ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl or C₃-C₁₀ cycloalkyl,which R₁ may be unsubstituted or substituted;

R₂ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, or C₃-C₁₀cycloalkyl, which R₂ may be unsubstituted or substituted; and R₁ and R₂may be taken together to form a ring or het;

R₃ and R₃′ are independently H, CF₃, C₂F₅, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, CH₂—Z, or R₂ and R₃ form het, wherein alkyl, alkenyl,alkynyl or het may be unsubstituted or substituted; and Z is H, OH, F,Cl, CH₃, CH₂Cl, CH₂F or CH₂OH;

D₁ and D₂ are independently C, CH, or N, wherein at least one of D₁ orD₂ is N;

each Q is independently H, F, Cl, Br, I, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy,aryl C₁-C₁₀ alkoxy, het C₁-C₁₀ alkoxy, OH, O—C₁-C₁₀-alkyl,(CH₂)₀₋₆—C₃-C₇ cycloalkyl, aryl, het, aryl C₁-C₁₀ alkyl, het C₁-C₁₀alkyl, O—(CH₂)₀₋₆ aryl, O—(CH₂)₀₋₆ het, —OR₁₁, C(O)R₁₁,—C(O)N(R₁₁)(R₁₂), N(R₁₁)(R₁₂), SR₁₁, S(O)R₁₁, S(O)₂R₁₁,S(O)₂—N(R₁₁)(R₁₂), NR₁₁—C(O)—R₁₂, or NR₁₁—S(O)₂—R₁₂, wherein alkyl,cycloalkyl, aryl and het are unsubstituted or substituted, n is 0, 1, or2, and independent Q's may be joined to form a 5-10 membered ring;

M is C(R₄)(R₅), C(O), C(S), S, S(O), S(O)₂, O, N(R₄), or a bond;

U is selected from:

(a) CON(R₆)(R₇), CN(R₆)(R₇), SO_(m), N(R₆)(R₇), R₄, C(R₄)(R₅)O(R₆),C(R₄)(R₅) S(O)_(m)R₆, C(R₄)(R₅)N(R₆)(R₇), N(R₆)(R₇), O(R₆), wherein m is0, 1, or 2;

R₄, R₅, R₆ and R₇ are independently H, halo, C₀₋₁₀ alkyl, C₀₋₁₀alkyl-aryl, C₀₋₁₀ alkyl-het, (CH₂)₀₋₆—C₃-C₇cycloalkyl,(CH₂)₀₋₆—C₃-C₇cycloalkyl-aryl, (CR₄R₅)₀₋₆—(CH)₀₋₁(aryl)₁₋₂, or(CR₄R₅)₀₋₆—(CH)₀₋₁(het)₁₋₂, wherein independent R₄, R₅, R₆, and R₇ maybe substituted or unsubstituted and may be joined to form a 4-10membered ring; or

(b)

wherein A is an aromatic ring, a 5-7 het or an 8-12 membered fused ringsystem that may include an aromatic ring, or one 5-7 het containing 1,2, or 3 heteroring atoms selected from N, O and S, which any position ofthe rings is unsubstituted or substituted with one or more Q's;

D is selected from

(a) a bond, —CO—, —C(O)—C₁₋₇ alkylene or arylene, —CF₂—, —O—, —S(O)_(m),1,3-dioxolane, C₁₋₇ alkyl-OH, where alkyl, alkylene or arylene may beunsubstituted or substituted with one or more halogens, OH,—O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃ wherein m is 0, 1, or 2; or

(b) —N(R₁₅) wherein R₁₅ is H, C₁₋₇ alkyl (unsubstituted or substituted),aryl, het, —O(C₁₋₇cycloalkyl) (unsubstituted or substituted),0(C₁₋₇alkyl) (unsubstituted or substituted), C(O)—C₁-C₁₀alkyl,C(O)—C_(o)—C₁₀alkyl-aryl, C(O)C₁-C₁₀alkyl, C—(O)—C_(o)—C₁₀alkyl-het,SO₂—C₁-C₁₀-alkyl, SO₂—(C_(o)—C₁₀-alkylaryl), orSO₂—(C_(o)—C₁₀-alkylhet);

Each Y is independently H, F, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, aryl C₁-C₁₀alkoxy, het C₁-C₁₀ alkoxy, OH, O—C₁-C₁₀-alkyl, (CH₂)₀₋₆—C₃-C₇cycloalkyl, aryl, het, aryl C₁-C₁₀ alkyl, het C₁-C₁₀ alkyl, O—(CH₂)₀₋₆aryl, (CH₂)₁₋₆ aryl, (CH₂)₁₋₆het, O—(CH₂)₀₋₆het, —OR₁₁, C(O)R₁₁,—C(O)N(R₁₁)(R₁₂), N(R₁₁)(R₁₂), SR₁₁, S(O)R₁₁, S(O)₂R₁₁,S(O)₂—N(R₁₁)(R₁₂), or NR₁₁—S(O)₂—(R₁₂), wherein alkyl, cycloalkyl aryl,het are unsubstituted or substituted; and each p is independently 0, 1,2, 3, 4, 5, 6, 7, 8, 9 or 10;

Q together with R₄, R₆ or Y may form a ring;

X is H, aryl, cycloalkyl, het, or an 8-12 membered fused ring systemthat may include an aromatic ring, or one 5-7 het containing 1, 2, or 3heteroring atoms selected from N, O and S, in which any may substitutedor unsubstituted, in which substituents on aryl, cycloalkyl and het arealkyl, halo, lower alkoxy, N(R₅)R₆, CN, NO₂, O Q together with R₄, R₆ orY may form a ring R₅, S(O)_(y)R₅, C(O)N(R₅)R₆, S(O)_(y)N(R₅)R₆;N(R₅)C(O)R₆, or N(R₅)S(O)_(y)R₆, wherein y is 0, 1, or 2;

het is a 5-7 membered monocyclic heterocyclic ring (aromatic ornon-aromatic) containing 1-4 heteroring atoms selected from N, O, and S;or an 8-12 membered fused ring system that includes one 5-7 memberedheterocyclic ring (aromatic or non-aromatic) containing 1, 2, or 3heteroring atoms selected from N, O and S, which het is unsubstituted orsubstituted;

R₁₁ and R₁₂ are independently H, C₁-C₁₀ alkyl, (CH₂)₀₋₆—C₃-C₇cycloalkyl,(CH₂)₀₋₆—(CH)₀₋₁(aryl)₁₋₂, C(O)—C₁-C₁₀alkyl,—C(O)—(CH₂)₁₋₆—C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆-aryl,—C(O)—(CH₂)₀₋₆—O-fluorenyl, C(O)—NH—(CH₂)₀₋₆-aryl, C(O)—(CH₂)₀₋₆-aryl,C(O)—(CH₂)₁₋₆-het, —C(S)—C₁-C₁₀alkyl, —C(S)—(CH₂)₁₋₆—C₃-C₇cycloalkyl,—C(S)—O—(CH₂)₀₋₆-aryl, —C(S)—(CH₂)₀₋₆—O-fluorenyl,C(S)—NH—(CH₂)₀₋₆-aryl, —C(S)—(CH₂)₀₋₆-aryl, C(S)—(CH₂)₁₋₆-het, C(O)R₁₁,C(O)NR₁₁R₁₂, C(O)OR₁₁, S(O)_(m), R₁₁, S(O)_(m)NR₁₁R₁₂, C(S)R₁₁,C(S)NR₁₁R₁₂, or C(S)OR₁₁, and m=0, 1 or 2, wherein alkyl, cycloalkyl andaryl are unsubstituted or substituted; or R₁₁ and R₁₂ are a substituentthat facilitates transport of the molecule across a cell membrane; orR₁₁ and R₁₂ together with the nitrogen atom form het; wherein the alkylsubstituents of R₁₁ and R₁₂ may be unsubstituted or substituted by oneor more substituents selected from C₁-C₁₀alkyl, halogen, OH,O—C₁-C₆alkyl, —S—C₁-C₆alkyl, CF₃ or NR₁₁R₁₂; and substituted cycloalkylsubstituents of R₁₁ and R₁₂ are substituted by one or more substituentsselected from a C₂-C₁₀ alkene, C₁-C₆alkyl, halogen, OH, O—C₁-C₆alkyl,S—C₁-C₆alkyl, CF₃, or NR₁₁R₁₂; and substituted het or substituted arylof R₁₁ and R₁₂ are substituted by one or more substituents selected fromhalogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, CN,O—C(O)—C₁-C₄alkyl, or C(O)—O—C₁-C₄-alkyl;

wherein the substituents on R₁, R₂, R₃, R₄, R₅, R₆, R₇, Q, A, and Xgroups are independently halo, hydroxy, lower alkyl, lower alkenyl,lower alkynyl, lower alkanoyl, lower alkoxy, aryl, aryl lower alkyl,amino, amino lower alkyl, diloweralkylamino, lower alkanoyl, amino loweralkoxy, nitro, cyano, cyano lower alkyl, carboxy, lower carbalkoxy,lower alkanoyl, aryloyl, lower arylalkanoyl, carbamoyl, N-mono- orN,N-dilower alkyl carbamoyl, lower alkyl carbamic acid ester, amidino,guanidine, ureido, mercapto, sulfo, lower alkylthio, sulfoamino,sulfonamide, benzosulfonamide, sulfonate, sulfanyl lower alkyl, arylsulfonamide, halogen substituted aryl sulfonate, lower alkylsulfinyl,arylsulfinyl; aryl-lower alkylsulfinyl, lower alkylarylsulfinyl, loweralkyl-sulfonyl, arylsulfonyl, aryl-lower alkylsulfonyl, loweralkylarylsulfinyl, lower alkyl-sulfonyl, arylsulfonyl, aryl-loweralkylsulfonyl, lower aryl alkyl lower alkylarylsulfonyl, halogen-loweralkylmercapto, halogen-lower alkylsulfonyl, phosphono (—P(═O)(OH)₂),hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl,(R₉)NC(O)—NR₁₀R₁₃, lower alkyl carbamic acid ester or carbamates or—NR₈R₁₄, wherein R₈ and R₁₄ can be the same or different and areindependently H or lower alkyl, or R₈ and R₁₄ together with the N atomform a 3- to 8-membered heterocyclic ring containing a nitrogenheteroring atoms and may optionally contain one or two additionalheteroring atoms selected from nitrogen, oxygen and sulfur, whichheterocyclic ring may be unsubstituted or substituted with lower alkyl,halo, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, nitro, amino,lower alkyl, amino, diloweralkyl amino, cyano, carboxy, lowercarbalkoxy, formyl, lower alkanoyl, oxo, carbarmoyl, N-lower orN,N-dilower alkyl carbamoyl, mercapto, or lower alkylthio, and R₉, R₁₀,and R₁₃ are independently hydrogen, lower alkyl, halogen substitutedlower alkyl, aryl, aryl lower alkyl, halogen substituted aryl, halogensubstituted aryl lower alkyl.

The present invention also relates to pharmaceutical compositionscomprising therapeutically effective amounts of compounds of Formula I,as defined hereinabove, or a pharmaceutically acceptable salt thereof,and a pharmaceutical carrier therefor. In another embodiment, thepresent invention is directed to a method of treating a mammal,especially human, afflicted with a proliferative disease, especiallythose dependent on the binding of the smac protein to Inhibitor ofApoptosis Proteins (IAPs), such as cancer, which method comprisesadministering to said mammal in need of treatment an anti-proliferativeeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof. The present invention is also directed to themanufacture of compounds of Formula I for use in the treatment of saiddiseases.

DETAILED DESCRIPTION

In an embodiment, the present invention relates to compounds accordingto formula I wherein R₁ is H, or C₁-C₄ alkyl, which R₁ may beunsubstituted or substituted; R₂ is H, or C₁-C₄ alkyl, which R₂ may beunsubstituted or substituted; R₁ and R₂ may be taken together to form aring or het; R₃ and R₃′ are independently H, CF₃, C₂F₅, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, CH₂—Z, or R₂ and R₃ taken together withthe nitrogen atom to which they are attached form het, wherein alkyl,alkenyl, alkynyl or het may be unsubstituted or substituted; and Z is H,OH, F, Cl, CH₃, CH₂Cl, CH₂F or CH₂OH. Each Q is independently H, F, Cl,Br, I, C₁-C₁₀ alkyl, (CH₂)₀₋₆—C₃-C₇ cycloalkyl, aryl, het, whereinalkyl, cycloalkyl, aryl and het are unsubstituted or substituted, n is0, 1, or 2, and independent Q's may be joined to form a 5-10 memberedring. M is C(R₄)(R₅), C(O), C(S), or a bond; and U is CON(R₆)(R₇),CN(R₆)(R₇), SO_(m)N(R₆)(R₇), R₄, C(R₄)(R₅)O(R₆), C(R₄)(R₅), orC(R₄)(R₅)N(R₆)(R₇).

In a further embodiment, the present invention relates to compoundsaccording to formula I wherein R₁ is H, or C₁-C₄ alkyl, which R₁ may beunsubstituted or substituted; R₂ is H, or C₁-C₄ alkyl, which R₂ may beunsubstituted or substituted. R₃ and R₃′ are independently H, or C₁-C₄alkyl; Q is aryl which is unsubstituted or substituted; M is C₁-C₄alkyl, C(O), or a bond; and U is C(O)N(R₆)(R₇), or CN(R₆)(R₇), whereinR₆ and R₇ independently are aryl, or cycloalkyl-het, and aryl orcycloalkyl-het may be unsubstituted or substituted.

In an embodiment, the present invention relates to compounds accordingto formula I wherein R₁ is H, or C₁-C₄ alkyl, which R₁ may beunsubstituted or substituted; R₂ is H, or C₁-C₄ alkyl, which R₂ may beunsubstituted or substituted; R₃ and R₃′ are independently H, or C₁-C₄alkyl; Q is benzene, or fluorobenzene; M is C₁-C₄ alkyl, C(O), or abond; and U is C(O)N(R₆)(R₇), or CN(R₆)(R₇), wherein R₆ and R₇independently are tetrahydro-napthalene (tetralin), or fluorobenzene.

In another embodiment, the present invention relates to compoundsaccording to formula I wherein: R₁ is H, or C₁-C₄ alkyl, which R₁ may beunsubstituted or substituted; R₂ is H, or C₁-C₄ alkyl, which R₂ may beunsubstituted or substituted; R₃ and R₃′ are independently H, or C₁-C₄alkyl; Q is aryl which may be unsubstituted or substituted. M is C₁-C₄alkyl, C(O), or a bond; and U is aryl-V-aryl, het-V-aryl, or aryl-V-het,wherein V is C(O), N(R₁₅), het, O, or a bond. In an embodiment, Q isbenzene or fluorobenzene, and the het group of U is pyridine orthiazole; and the aryl group of U is fluorobenzene, benzene, or benzenefused with dioxolane. In another embodiment, the het group of U is afive membered ring with N as the heterocyclic atom, and may be aromaticor non-aromatic.

In another embodiment, the present invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I. The pharmaceutical composition may also include apharmaceutically acceptable carrier. In a further embodiment, thepresent invention also provides a method of treating a mammal sufferingfrom a proliferative disease. The method includes administering to themammal in need of treatment a therapeutically effective amount of acompound according to formula I. In a further embodiment, the presentinvention includes a method of inhibiting cell proliferation. The methodincludes administering an effective amount of the compound according toformula I to inhibit cell proliferation to a cell or mammal in needthereof.

As used herein, the term “Aryl” is defined as an aromatic radical having6 to 14 ring carbon atoms, and no ring heteroatoms. The aryl group maybe monocyclic or fused bicyclic or tricyclic. It may be unsubstituted orsubstituted by one or more, preferably one or two, substituents, whereinthe substituents are as described herein. As defined herein, the arylmoiety may be completely aromatic regardless of whether it is monocyclicor bicyclic. However, if it contains more than one ring, as definedherein, the term aryl includes moieties wherein at least one ring iscompletely aromatic while the other ring(s) may be partially unsaturatedor saturated or completely aromatic

“Het” as used herein, refers to heteroaryl and heterocyclic compoundscontaining at least one S, O or N ring heteroatom. More specifically,“Het” is a 5-7 membered heterocyclic ring containing 1-4 heteroatomsselected from N, O and S, or an 8-12 membered fused ring systemincluding at least one 5-7 membered heterocyclic ring containing 1, 2 or3 heteroatoms selected from N, O, and S. Examples of het, as usedherein, include but are not limited to unsubstituted and substitutedpyrrolidyl, tetrahydrofuryl, tetrahydrothiofuryl, piperidyl, piperazyl,purinyl, tetrahydropyranyl, morpholino, 1,3-diazapanyl, 1,4-diazapanyl,1,4-oxazepanyl, 1,4-oxathiapanyl, furyl, thienyl, pyrryl, pyrrolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, oxadiazolyl, imidazolyl,pyrrolidyl, pyrrolidinyl, thiazolyl, oxazolyl, pyridyl, pyrazolyl,pyrazinyl, pyrimidinyl, isoxazolyl, pyrazinyl, quinolyl, isoquinolyl,pyridopyrazinyl, pyrrolopyridyl, furopyridyl, indolyl, benzofuryl,benzothiofuryl, benzoindolyl, benzothienyl, pyrazolyl, piperidyl,piperazinyl, indolinyl, morpholinyl, benzoxazolyl, pyrroloquinolyl,pyrrolo[2,3-b]pyridinyl, benzotriazolyl, oxobenzo-oxazolyl,benco[1,3]dioxolyl, benxzoimidazolyl, quinolinyl, indanyl and the like.Heteroaryls are within the scope of the definition of het. Examples ofheteroaryls are pyridyl, pyrimidinyl, quinolyl, thiazolyl andbenzothiazolyl. The most preferred het are pyridyl, pyrimidinyl andthiazolyl. The het may be unsubstituted or substituted as describedherein. It is preferred that it is unsubstituted or if substituted it issubstituted on a carbon atom by halogen, especially fluorine orchlorine, hydroxy, C₁-C₄ alkyl, such as methyl and ethyl, C₁-C₄ alkoxy,especially methoxy and ethoxy, nitro, —O—C(O)—C₁-C₄alkyl or—C(O)—O—C₁-C₄alkyl, SCN or nitro or on a nitrogen atom by C₁-C₄ alkyl,especially methyl or ethyl, —O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄alkyl,such as carbomethoxy or carboethoxy.

When two substituents together with a commonly bound nitrogen are het,it is understood that the resulting heterocyclic ring is anitrogen-containing ring, such as aziridine, azetidine, azole,piperidine, piperazine, morphiline, pyrrole, pyrazole, thiazole,oxazole, pyridine, pyrimidine, isoxazole, and the like, wherein such hetmay be unsubstituted or substituted as defined hereinabove.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorineand chlorine.

Unless otherwise specified “alkyl”, either above or in combination,includes straight or branched chain alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andbranched pentyl, n-hexyl and branched hexyl, and the like.

A “cycloalkyl” group means C₃ to C₁₀ cycloalkyl having 3 to 10 ringcarbon atoms and may be, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, cyclononyl and thelike. The cycloalkyl group may be monocyclic or fused bicyclic.Moreover, the preferred cycloalkyl group is cyclopentyl or cyclohexyl.Most preferably, cycloalkyl is cyclohexyl. The cycloalkyl group may befully saturated or partially unsaturated, although it is preferred thatit is fully saturated. As defined herein, it excludes aryl groups. Thecycloalkyl groups may be unsubstituted or substituted with any of thesubstituents defined below, preferably halo, hydroxy or C₁-C₆ alkyl suchas methyl.

Substituents that facilitate transport of the molecule across a cellmembrane are known to those of skill in the medicinal chemistry arts(see, for example, Gangewar S., Pauletti G. M., Wang B., Siahaan T. J.,Stella V. J., Borchardt R. T., Drug Discovery Today, vol. 2. p 148-155(1997) and Bundgaard H. and Moss J., Pharmaceutical Research, vol. 7, p885 (1990)). Generally, such substituents are lipophillic substituents.Such lipophillic substituents include a C₆-C₃₀ alkyl which is saturated,monounsaturated, polyunsaturated, including methylene-interruptedpolyene, phenyl, phenyl which is substituted by one or two C₁-C₈ alkylgroups, C₅-C₉ cycloalkyl, C₅-C₉ cycloalkyl which is substituted by oneor two C₁-C₈ alkyl groups, —X₁-phenyl, —X₁-phenyl which is substitutedin the phenyl ring by one or two C₁-C₈ alkyl groups, X₁—C₅-C₉ cycloalkylor X₁—C₅-C₉ cycloalkyl which is substituted by one or two C₁-C₈ alkylgroups; where X₁ is C₁-C₂₄ alkyl which is saturated, monounsaturated orpolyunsaturated and straight or branched chain.

Unsubstituted is intended to mean that hydrogen is the only substituent.

Except as described herein, any of the above defined aryl, het, alkyl,alkenyl, alkynyl, or cycloalkyl, may be unsubstituted or independentlysubstituted by up to four, preferably one, two or three substituents,selected from the group consisting of: halo (such as Cl or Br); hydroxy;lower alkyl (such as C₁-C₃ alkyl); lower alkyl which may be substitutedwith any of the substituents defined herein; lower alkenyl; loweralkynyl; lower alkanoyl; lower alkoxy (such as methoxy); aryl (such asphenyl or naphthyl); substituted aryl (such as fluoro phenyl or methoxyphenyl); aryl lower alkyl such as benzyl, amino, mono or di-lower alkyl(such as dimethylamino); lower alkanoyl amino acetylamino; amino loweralkoxy (such as ethoxyamine); nitro; cyano; cyano lower alkyl; carboxy;lower carbalkoxy (such as methoxy carbonyl; n-propoxy carbonyl oriso-propoxy carbonyl), lower aryloyl, such as benzoyl; carbamoyl;N-mono- or N,N di-lower alkyl carbamoyl; lower alkyl carbamic acidester; amidino; guanidine; ureido; mercapto; sulfo; lower alkylthio;sulfoamino; sulfonamide; benzosulfonamide; sulfonate; sulfanyl loweralkyl (such as methyl sulfanyl); sulfoamino; aryl sulfonamide; halogensubstituted or unsubstituted aryl sulfonate (such as chloro-phenylsulfonate); lower alkylsulfinyl; arylsulfinyl; aryl-lower alkylsulfinyl;lower alkylarylsulfinyl; lower alkanesulfonyl; arylsulfonyl; aryl-loweralkylsulfonyl; lower aryl alkyl; lower alkylarylsulfonyl; halogen-loweralkylmercapto; halogen-lower alkylsulfonyl; such as trifluoromethanesulfonyl; phosphono(—P(═O)(OH)₂); hydroxy-lower alkoxy phosphoryl ordi-lower alkoxy-phosphoryl; urea and substituted urea; alkyl carbamicacid ester or carbamates (such as ethyl-N-phenyl-carbamate); or loweralkyl (e.g. methyl, ethyl or propyl).

In an embodiment, the above mentioned alkyl, cycloalkyl, and aryl groupsare independently unsubstituted or are substituted by lower alkyl, aryl,aryl lower alkyl, carboxy, lower carbalkoxy and especially halogen, —OH,—SH, —OCH₃, —SCH₃, —CN, —SCN or nitro.

As defined herein the term “lower alkyl”, when used alone or incombination refers to alkyl containing 1-6 carbon atoms. The alkyl groupmay be branched or straight-chained, and is as defined hereinabove.

The term “lower alkenyl” refers to a alkenyl group which contains 2-6carbon atoms. An alkenyl group is a hydrocarbyl group containing atleast one carbon-carbon double bond. As defined herein, it may beunsubstituted or substituted with the substituents described herein. Thecarbon-carbon double bonds may be between any two carbon atoms of thealkenyl group. It is preferred that it contains 1 or 2 carbon-carbondouble bonds and more preferably one carbon-carbon double bond. Thealkenyl group may be straight chained or branched. Examples include butare not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 2-methyl-1-propenyl, 1,3-butadienyl, and the like.

The term “lower alkynyl”, as used herein, refers to an alkynyl groupcontaining 2-6 carbon atoms. An alkynyl group is a hydrocarbyl groupcontaining at least one carbon-carbon triple bond. The carbon-carbontriple bond may be between any two carbon atom of the alkynyl group. Inan embodiment, the alkynyl group contains 1 or 2 carbon-carbon triplebonds and more preferably one carbon-carbon triple bond. The alkynylgroup may be straight chained or branched. Examples include but are notlimited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and thelike.

As used herein, the term “aryl alkyl” refers to a aryl group connectedto the main chain by a bridging alkylene group. Examples include but arenot limited to benzyl, phenethyl, naphthylmethyl, and the like.Similarly, cyano alkyl group refers to a cyano group connected to themain chain by a bridging alkylene group.

The term “alkyl aryl” on the other hand, refers to an alkyl groupbridged to the main chain through a phenylene group. Examples includebut are not limited to methylphenyl, ethylphenyl, and the like.

As used herein, the term lower alkanoyl refers to a lower alkyl chain inwhich one of the carbon atoms is replaced by a C═O group. The C═O groupmay be present at one of the ends of the substituent or in the middle ofthe moiety. Examples include but are not limited to formyl, acetyl,2-propanoyl, 1-propanoyl and the like.

The term “alkoxy” refers to an alkyl group as defined herein, connectedto the main chain by an oxygen atom. Examples include but are notlimited to methoxy, ethoxy, and the like.

The term “lower thioalkyl” refers to an alkyl group, as defined herein,connected to the main chain by a sulfur atom. Examples include but arenot limited to thiomethyl (or mercapto methyl), thioethyl (mercaptoethyl) and the like.

The term “lower carbalkoxy” or synonym thereto refers to analkoxycarbonyl group, where the attachment to the main chain is throughthe aryl group (C(O)). Examples include but are not limited to methoxycarbonyl, ethoxy carbonyl, and the like.

It is to be understood that the terminology C(O) refers to a —C═O group,whether it be ketone, aldehyde or acid or acid derivative. Similarly,—S(O) refers to a —S═O group.

As discussed above, the compounds of the present invention are usefulfor treating proliferative diseases. Thus, the present invention furtherrelates to a method of treating a proliferative disease which comprisesadministering a therapeutically effective amount of a compound of theinvention to a mammal, preferably a human, in need of such treatment.

A proliferative disease is mainly a tumor disease (or cancer) (and/orany metastases). The inventive compounds are particularly useful fortreating a tumor which is a breast cancer, genitourinary cancer, lungcancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovariancancer, pancreas cancer, neuroblastoma, head and/or neck cancer orbladder cancer, or in a broader sense renal, brain or gastric cancer; inparticular (i) a breast tumor; an epidermoid tumor, such as anepidermoid head and/or neck tumor or a mouth tumor; a lung tumor, forexample a small cell or non-small cell lung tumor; a gastrointestinaltumor, for example, a colorectal tumor; or a genitourinary tumor, forexample, a prostate tumor (especially a hormone-refractory prostatetumor); or (ii) a proliferative disease that is refractory to thetreatment with other chemotherapeutics; or (iii) a tumor that isrefractory to treatment with other chemotherapeutics due to multidrugresistance.

In a broader sense of the invention, a proliferative disease mayfurthermore be a hyperproliferative condition such as leukemias,hyperplasias, fibrosis (especially pulmonary, but also other types offibrosis, such as renal fibrosis), angiogenesis, psoriasis,atherosclerosis and smooth muscle proliferation in the blood vessels,such as stenosis or restenosis following angioplasty.

Where a tumor, a tumor disease, a carcinoma or a cancer are mentioned,also metastasis in the original organ or tissue and/or in any otherlocation are implied alternatively or in addition, whatever the locationof the tumor and/or metastasis.

The inventive compound is selectively toxic or more toxic to rapidlyproliferating cells than to normal cells, particularly in human cancercells, e.g., cancerous tumors, the compound has significantantiproliferative effects and promotes differentiation, e.g., cell cyclearrest and apoptosis.

The present invention further relates to a method of promoting apoptosisin rapidly proliferating cells, which comprises contacting the rapidlyproliferating cells with an effective apoptosis promoting amount of anon-naturally-occurring compound that binds to the Smac binding site ofXIAP and/or cIAP proteins. Preferably, the non-naturally-occurringcompound is a compound of present formula I.

The invention relates also to pharmaceutical compositions comprising acompound of formula I, to their use in the therapeutic (in a broaderaspect of the invention also prophylactic) treatment or a method oftreatment of a kinase dependent disease, especially the preferreddiseases mentioned above, to the compounds for said use and topharmaceutical preparations and their manufacture, especially for saiduses.

The present invention also relates to pro-drugs of a compound of formulaI that convert in vivo to the compound of formula I as such. Anyreference to a compound of formula I is therefore to be understood asreferring also to the corresponding pro-drugs of the compound of formulaI, as appropriate and expedient.

The pharmacologically acceptable compounds of the present invention maybe present in or employed, for example, for the preparation ofpharmaceutical compositions that comprise an effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, as active ingredient together or in admixture with one or moreinorganic or organic, solid or liquid, pharmaceutically acceptablecarriers (carrier materials)

The invention relates also to a pharmaceutical composition that issuitable for administration to a warm-blooded animal, especially a human(or to cells or cell lines derived from a warm-blooded animal,especially a human, e.g. lymphocytes), for the treatment of (this, in abroader aspect of the invention, also includes the prevention of(=prophylaxis against)) a disease that responds to inhibition of proteinkinase activity, comprising an amount of a compound of formula I or apharmaceutically acceptable salt thereof, preferably which is effectivefor said inhibition, together with at least one pharmaceuticallyacceptable carrier.

The pharmaceutical compositions according to the invention are those forenteral, such as nasal, rectal or oral, or parenteral, such asintramuscular or intravenous, administration to warm-blooded animals(especially a human), that comprise an effective dose of thepharmacologically active ingredient, alone or together with asignificant amount of a pharmaceutically acceptable carrier. The dose ofthe active ingredient depends on the species of warm-blooded animal, thebody weight, the age and the individual condition, individualpharmacokinetic data, the disease to be treated and the mode ofadministration.

The invention relates also to a method of treatment for a disease thatresponds to inhibition of a protein kinase and/or a proliferativedisease, which comprises administering a (against the mentioneddiseases) prophylactically or especially therapeutically effectiveamount of a compound of formula I according to the invention, or atautomer thereof or a pharmaceutically acceptable salt thereof,especially to a warm-blooded animal, for example a human, that, onaccount of one of the mentioned diseases, requires such treatment.

The dose of a compound of the formula I or a pharmaceutically acceptablesalt thereof to be administered to warm-blooded animals, for examplehumans of approximately 70 kg body weight, preferably is fromapproximately 3 mg to approximately 10 g, more preferably fromapproximately 10 mg to approximately 1.5 g, most preferably from about100 mg to about 1000 mg/person/day, divided preferably into 1-3 singledoses which may, for example, be of the same size. Usually, childrenreceive half of the adult dose.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragées, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional dissolving,lyophilizing, mixing, granulating or confectioning processes.

The compounds of the present invention are prepared as depicted below inscheme 1. For example, compounds of formula (I) are prepared by reactinga carboxylic acid or acylating derivative thereof, such as an acidhalide of formula (II) with an amine of formula (III) under amideforming conditions:

wherein R is a protecting group or R₁; R₁, R₂, R₃, R₃′, Q, n, D₁, D₂, Mand U are as defined hereinabove.

The compound of formula (II) is either commercially-available or isprepared from formula (IV):

in which the amino group is reacted with an amino protecting group underconditions known to one of ordinary skill in the art. The compound offormula (III) is either commercially-available or prepared by artrecognized techniques or may be prepared as depicted below in scheme 2.

wherein formulae (V), (VII), (VIII) and (IX) are either commerciallyavailable or prepared by art recognized techniques or as the schemeabove shown, is a leaving group; P1 and P2 are protecting groups.

If any group on the reactants is reactive under the conditions describedit is protected by a protecting group known in the art, prior toconducting the reactions described hereinabove and then removed afterthe reaction is effected. Protecting groups normally used in thesereactions are described in a book entitled Protective Groups in OrganicSynthesis, Theodora W. Greene, John Wiley & Sons, NY, N.Y. (1981), thecontents of which are incorporated by reference.

EXAMPLES

The following examples are intended to illustrate, but not furtherlimit, the invention. The following compounds are prepared by methodsanalog to those described herein utilizing analogous starting materials:

5 (2methylamino-propionamidyl)-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl-N-tetrahedron-naphthoyl)-acetamide(example 29 of table 2). The synthesis of the title compound (example29) is carried out according to the procedures set forth in scheme 3below:

[5-[(Benzyloxycarbonyl)amino]-6-oxo-2-(phenyl)-1,6-dihydro-1-pyrimidinyl]-N-tetrahedro-naphthoyl)acetamide(B)

To a solution of the acid A (Veale, C. A. et. al. J. Med. Chem. 1995,38, 98-108) (379 mg, 1 mmol), 1-hydroxybenzotriazole hydrate (203 mg,1.5 mmol), and triethylamine (202 mg, 2 mmol) in DMF (5 mL) was addedEDC (356 mg, 1.2 mmol), and the solution was stirred for 0.5 h.(R)-(1,2,3,4-Tetrahydro-naphthalen-1-yl)amine (147 mg, 1 mmol) wasadded, and the solution was stirred for 16 h. Then the solution wasdiluted with H₂O and extracted with ethyl acetate, washed with asaturated aqueous solution of ammonium chloride (2×25 mL). The solutionwas dried and the solvent removed. The resulting oil crystallized uponstanding and was collected and dried to give the titled amide B (383 mg,75%) as a white solid: ¹H NMR (400 MHz, CDCl₃): δ 8.75 (1H, s), 7.62(2H, m), 7.51 (4H, m), 7.37 (5H, m), 7.16 (4H, m), 6.08 (1H, d), 5.22(2H, s), 5.20 (1H, m), 4.56 (2H, s), 2.74 (2H, t), 1.78 (4H, m); MS: 509(M+H⁺).

5-aminol-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl-N-tetrahedron-naphthoyl)-acetamide(C)

Compound B (383 mg, 0.755 mmol) was dissolved in ethanol (5 mL) and tothis solution was added 10% Pd/C (10 mg). The suspension was shakenunder a hydrogen atmosphere (45 psi) for 4 hrs. The mixture was filteredfree of catalyst and the solvent removed, yielding product 11 (268 mg,95%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃): δ 7.58 (2H, m),7.48 (4H, m), 7.23 (1H, m), 7.19 (2H, m), 7.11 (1H, m), 6.08 (1H, d),5.20 (1H, m), 4.56 (2H, s), 4.03 (2H, s), 2.78 (2H, m), 2.08 (1H, m),1.82 (3H, m); MS: 375 (M+H⁺).

5-(2-methylamino-propionamidyl)-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl-N-tetrahedron-naphthoyl)-acetamide(Example No. 29)

To a solution of the (S)-Boc-N-Me-Ala (65 mg, 0.32 mmol) in DMF (2.5 mL)was added HATU (150 mg, 0.38 mmol), and DIPEA (82 mg, 0.64 mmol), andthe solution was stirred for 0.5 h. Then amine C (100 mg, 0.267 mmol)was added, and the solution was stirred for 16 h. Then the solution wasdiluted with H₂O and extracted with ethyl acetate (3×50 mL), then washedwith a saturated aqueous solution of ammonium chloride (2×20 mL). Thesolution was dried and the solvent removed. The resulting oil wascarried over to next step. The crude product was dissolved indichloromethane (3 mL). To this solution was added 4N HCl in dioxane (2mL). The reaction mixture was stirred for 10 h; then solvent wasremoved, and the resulting oil was purified by preparative HPLC to givethe tiled product, example no. 29 (96 mg, 52% in two steps) as a TFAsalt and as a white solid: ¹H NMR (400 MHz, MeOD): δ 8.87 (1H, s), 8.51(1H, d), 7.48 (5H, m), 7.04 (4H, m), 5.01 (1H, m), 4.57 (2H, m), 4.20(1H, q), 2.72 (5H, m), 1.85 (4H, m), 1.65 (3H, d); MS: 460 (M+H⁺).

(S)-2-Methylamino-N-(3-oxo-5-phenyl-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-propionamide(example no. 30). The synthesis of the title compound (example 30) iscarried out according to the procedures set forth in scheme 4 below:

3-Methoxy-5-phenyl-pyrazin-2-ylamine (B)

5-Bromo-3-methoxy-pyrazin-2-ylamine (A) (816 mg, 4 mmol) and phenylboronic acid (732 mg, 6 mmol) in toluene (5 mL), ethanol (5 mL) andNa₂CO₃ (8 mmol, 1 M aqueous) was purged with nitrogen for 10 minutes,and was added PdCl₂(PPh₃)₂(140 mg, 0.2 mmol). The reaction mixture wasstirred at 85° C. for 4 hours. The reaction mixture was cooled to roomtemperature and diluted with EtOAc (50 mL). The solution was washed withbrine (2×5 mL). The organic extracts was dried with MgSO₄, then solventwas removed under vacuum. The residue was purified with flash column togive product B (660 mg, 82%) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ8.08 (1H, s), 7.92 (2H, d), 7.46 (3H, m), 4.94 (2H, bs), 4.12 (3H, s);MS: 202 (M+H⁺).

6-Phenyl-3-amino-2-oxo-hydro-pyrazine (C)

Aniline B (100 mg, 0.5 mmol) was dissolved in glacial acetic acid (1 mL)and HBr (1 mL). The mixture was heated at 110° C. for 4 hrs. Solidcrushed out and was collected by filtration to afford pyrazinone C aswhite solid (88 mg, 95%). ¹H NMR (400 MHz, DMSO): δ 12.21 (1H, s), 7.82(2H, d), 7.61 (2H, d), 7.44 (3H, m), 7.03 (1H, s). MS: 188 (M+H⁴).

3-(2-Methylamino-propionamidyl)-6-phenyl-2-oxo-hydro-pyrazine (D)

To a solution of (S)-Boc-N-Me-Ala (244 mg, 1.2 mmol) in DMF (2.5 mL) wasadded HATU (547 mg, 1.44 mmol), and DIPEA (310 mg, 2.4 mmol), and thesolution was stirred for 0.5 h. Then amine C (187 mg, 1 mmol) in DMF (5mL) was added, and the solution was stirred for 16 h. Then the solutionwas diluted with H₂O and extracted with CH₂Cl₂, The solution was driedand the solvent removed. The crude product was purified bychromatography to afford the title compound D as white solid (255 mg,68%): NMR (400 MHz, DMSO): δ 7.68 (2H, m), 7.51 (3H, m), 7.37 (1H, s),4.85 (1H, bs), 2.95 (3H, s), 1.48 (12H, b); MS: 373 (M+H⁺).

3-(2-Boc-Methylamino-propionamidyl)-6-phenyl-2-oxo-hydro-pyrazyl-1-N-tetrahedron-naphthoyl)-acetamide(E)

To a solution of pyrazinone D (250 mg, 0.67 mmol) in DME (10 mL) and DMF(1 mL), was added2-iodo-N—(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-acetamide (100 mg, 0.67)and LiH (6.4 mg, 0.8 mmol). The mixture was heated at 60° C. for 10 hrs.Then the solution was diluted with H₂O and extracted with CH₂Cl₂, Thesolution was dried and the solvent removed. The residue was purified byflash column to give desired product E (90 mg): MS: 560 (M+H⁺).

(S)-2-Methylamino-N-(3-oxo-5-phenyl-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-propionamide(example no. 30)

Compound E (90 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL).To this was added 4N HCl in dioxane (2 mL). The reaction mixture wasstirred for 10 h; then solvent was removed, and the resulting oil waspurified by HPLC to give the title product, example no. 30 of table 2.(35 mg, 8% in two steps) as a TFA salt and as a white solid: ¹H NMR (400MHz, MeOD): δ 8.47 (1H, d), 7.42 (5H, m), 6.98 (5H, m), 5.01 (1H, m),4.51 (3H, m), 2.67 (5H, m), 1.81 (4H, m), 1.57 (3H, d); MS: 460 (M+H⁺).

TABLE 1 EXAMPLE MS ESI STRUCTURE NO. NAME (M + H)+

1(S)-N-(5-(4-Fluoro-phenyl)-3-oxo-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-y1)-2-methylamino-propionamide 478.5

2(S)-N-(2-(4-Fluoro-phenyl)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-2- methylamino-propionamide 478.5

3(S)-N-{5-(4-Fluoro-phenyl)-4-[2-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-amino)-acetyl]-3-oxo-3,4-dihydro-pyrazin-2-y1}-2-methylamino-propionamide 492.6

4(S)-N-{5-(4-Fluoro-phenyl)-4-[2-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-amino)-ethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide478.6

5(S)-N-{2-(4-Fluoro-phenyl)-1-[2-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-amino)-acetyl]-6-oxo-1,6-dihydro-pyrimidin-5-y1}-2-methylamino-propionamide 492.6

6(S)-N-{2-(4-Fluoro-phenyl)-1-[2-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-amino)-ethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 478.6

7(S)-N-[4-[(4-Fluoro-benzylcarbamoyl)-methyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide456.5

8(S)-N-[1-[(4-Fluoro-benzylcarbamoyl)-methyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide 456.5

9 (S)-N-[4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-di-hydro-pyrazin-2-yl]-2-methylamino- propionamide 504.5

10 (S)-N-[1-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino- propionamide 504.5

11(S)-N-[4-[5-(4-Fluoro-benzoyl)-pyridin-3-yl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide490.5

12(S)-N-[1-[5-(4-Fluoro-benzoyl)-pyridin-3-yl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide490.5

13 (S)-N-(5-(4-Fluoro-phenyl)-4-{5-[(4-fluoro-phenyl)-methyl-amino]-pyridin-3-ylmethyl}-3-oxo-3,4-dihydro-pyrazin-2-yl)-2-methylamino- propionamide 505.5

14 (S)-N-(2-(4-Fluoro-phenyl)-1-{5-[(4-fluoro-phenyl)-methyl-amino]-pyridin-3-ylmethyl}-6-oxo-1,6-dihydro-pyrimidin-5-yl)-2-methylamino- propionamide 505.5

15(S)-N-[4-[5-(5-Fluoro-2,3-dihydro-indol-1-yl)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide 517.6

16(S)-N-[1-[5-(5-Fluoro-2,3-dihydro-indol-1-yl)-pyridin-3-ylmethyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide 517.6

17 (S)-N-[4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino- propionamide 529.6

18 (S)-N-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino- propionamide 529.6

19 (S)-N-{5-(4-Fluoro-phenyl)-4-[1-(4-fluoro-phenyl)-1H-indol-4-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino- propionamide 514.2

20 (S)-N-{2-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-1-indol-4-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 514.2

21 (S)-N-[4-(5-Benzo[1,3]dioxol-5-yl-pyridin-3-ylmethyl)-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino- propionamide 502.5

22 (S)-N-[1-(5-Benzo[1,3]dioxol-5-yl-pyridin-3-ylmethyl)-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino- propionamide 512.5

23 (S)-N-[4-[5-(4-Fluoro-phenoxy)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino- propionamide 492.6

24 (S)-N-[1-[5-(4-Fluoro-phenoxy)-pyridin-3-ylmethyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino- propionamide 492.6

25 (S)-N-{4-[4-(4-Fluoro-benzoyl)-thiazol-2-ylmethyl]-3-oxo-5-phenyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 492.5

26 (S)-N-[4-[4-(4-Fluoro-benzoyl)-thiazol-2-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino- propionamide 510.5

27 (S)-N-[1-[4-(4-Fluoro-benzoyl)-thiazol-2-ylmethyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino- propionamide 510.5

28 (S)-N-{1-[4-(4-Fluoro-benzoyl)-thiazol-2-ylmethyl]-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 492.5

TABLE 2 MS ESI Structure Example No. name (M + H)+

29(S)-2-Methylamino-N-(6-oxo-2-phenyl-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-propionamide 460.2

30(S)-2-Methylamino-N-(3-oxo-5-phenyl-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-propionamide 460.2

31 (S)-N-(2-(3-Trifluoromethyl-phenyl)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-2-methylamino-propionamide 528.2

32 (S)-N-(5-(3-Trifluoromethyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2- methylamino-propionamide528.2

33(S)-N-{2-(4-Fluoro-phenyl)-1-[((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-carbamoyl)-methyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide492.2

34(S)-N-{5-(4-Fluoro-phenyl)-4-[((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-carbamoyl)-methyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide492.2

35 (S)-2-Methylamino-N-(6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-2-o-tolyl-1,6-dihydro-pyrimidin-5-yl)-propionamide 474.2

36 (S)-2-Methylamino-N-(3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-5-o-tolyl-3,4-dihydro-pyrazin-2-yl)-propionamide 474.2

37 (S)-N-(2-(4-Fluoro-2-methyl-phenyl)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-2-methylamino-propionamide 492.2

38 (S)-N-(5-(4-Fluoro-2-methyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2- methylamino-propionamide492.2

39 (S)-N-(2-(2,4-Dimethyl-phenyl)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-2-methylamino- propionamide 488.3

40(S)-N-(5-(2,4-Dimethyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2-methylamino- propionamide 488.3

41 (S)-N-(2-(4-Fluoro-2-methyl-phenyl)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-2-methylamino- butyramide506.2

42 (S)-N-(5-(4-Fluoro-2-methyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2-methylamino- butyramide506.2

43(S)-N-(2-(4-Cyano-phenyl)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-5-yl)-2-methylamino-propionamide 485.2

44 N-Methyl-3-(5-((S)-2-methylamino-propionylamino)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-2-yl)-benzamide 518.3

45 N,N-Dimethyl-3-(5-((S)-2-methylamino-propionylamino)-6-oxo-1-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-1,6-dihydro-pyrimidin-2-yl)-benzamide 531.3

46 (S)-N-(2-(4-Fluoro-phenyl)-1-{[2-(4-fluoro-phenyl)-ethylcarbamoyl]-methyl}-6-oxo-1,6-dihydro-pyrimidin-5-yl)-2-methylamino- propionamide 470.2

47(S)-N-[1-[(1-Benzyl-2-phenyl-ethylcarbamoyl)-methyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide541.2

48(S)-N-[4-[(1-Benzyl-2-phenyl-ethylcarbamoyl)-methyl]-2-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide541.2

49(S)-N-[1-[(Diphenethylcarbamoyl)-methyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide556.3

50(S)-N-[4-[(Diphenethylcarbamoyl)-methyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide556.3

51(S)-N-[1-(2-Carbazol-9-yl-2-oxo-ethyl)-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide 498.2

52(S)-N-[4-(2-Carbazol-9-yl-2-oxo-ethyl)-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide 498.2

53(S)-N-[4-[2-(1,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide450.2

54(S)-N-[1-[2-(1,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide 450.2

55(S)-N-{2-(4-Fluoro-phenyl)-1-[2-(indan-2-yloxy)-ethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 451.2

56(S)-N-{5-(4-Fluoro-phenyl)-4-[2-(indan-2-yloxy)-ethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 451.2

57(S)-N-[2-(4-Fluoro-phenyl)-6-oxo-1-(2-phenethylsulfanyl-ethyl)-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide 455.2

58(S)-N-{2-(4-Fluoro-phenyl)-6-oxo-1-[2-(2-phenyl-ethanesulfonyl)-ethyl]-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide487.2

59(S)-N-{2-Benzo[1,3]dioxol-5-yl-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide530.2

60(S)-N-{5-Benzo[1,3]dioxol-5-yl-4-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide530.2

613-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide 568.2

623-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide 568.2

633-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide582.3

643-[1-(5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide582.3

65S)-N-{2-(3-Cyano-phenyl)-1-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 595.2

66 (S)-N-{5-(3-Cyano-phenyl)-4-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino- propionamide 595.2

67(S)-N-{2-Cyclohex-1-enyl-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide490.2

68 (S)-N-{2-(3-Cyano-phenyl)-1-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino- propionamide 536.2

69 (S)-N-{5-(3-Cyano-phenyl)-4-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino- propionamide 536.2

70 3-[1-[3-(4-Fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl- benzamide 627.3

71 3-[1-[3-(4-Fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl- benzamide 627.3

72N-Ethyl-3-[1-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-benzamide641.3

73 3-[1-[3-(4-Fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-isobutyl- benzamide 669.3

74(S)-N-{5-(3-Acetylamino-phenyl)-4-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide543.2

75 (S)-N-{1-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-6-oxo-2-o-tolyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 500.2

76 (S)-N-{4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 500.2

77 (S)-N-{1-[5-(5-Fluoro-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-o-tolyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 511.2

78 (S)-N-{4-[5-(5-Fluoro-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 511.2

793-[1-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide543.2

803-[1-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide543.2

81 (S)-N-[4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-(4-methoxy-pyridin-3-yl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino- propionamide 517.2

82(S)-N-{2-Benzo[1,2,5]oxadiazol-5-yl-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 528.2

83(S)-N-{5-Benzo[1,2,5]oxadiazol-5-yl-4-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 528.2

84(S)-N-{2-Benzo[1,2,5]oxadiazol-5-yl-1-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide553.2

85(S)-N-{5-Benzo[1,2,5]oxadiazol-5-yl-4-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide553.2

86 (S)-N-{1-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2- methylamino-propionamide410.2

87 (S)-N-{4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2- methylamino-propionamide410.2

88[5-((S)-2-Methylamino-propionylamino)-6-oxo-2-phenyl-6H-pyrimidin-1-yl]-aceticacid 1,2,3,4- tetrahydro-naphthalen-1-yl ester 461.2

89[3-((S)-2-Methylamino-propionylamino)-2-oxo-6-phenyl-2H-pyrazin-1-yl]-aceticacid 1,2,3,4- tetrahydro-naphthalen-1-yl ester 461.2

90(S)-N-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-(2-pyrrolidin-1-yl-pyridin-4-yl)-1,6-dihydro-pyrimidin-5-yl]-2-methylamino-propionamide581.3

91(S)-N-[4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-(2-pyrrolidin-1-yl-pyridin-4-yl)-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide 581.3

92 (S)-N-{1-[5-(5-Fluoro-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 497.2

93 (S)-N-{4-[5-(5-Fluoro-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-phenyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 497.2

94 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-phenyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 511.2

95 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-phenyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 511.2

96 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-[3-(2H-tetrazol-5-yl)-phenyl]-1,6-dihydro-pyrimidin-5-yl}-2- methylamino-propionamide579.2

97 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-[4-(1H-tetrazol-5-yl)-phenyl]-1,6-dihydro-pyrimidin-5-yl}-2- methylamino-propionamide579.2

98 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[3-(2H-tetrazol-5-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2- methylamino-propionamide 579.2

99 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[4-(1H-tetrazol-5-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2- methylamino-propionamide 579.2

100 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-2-[3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 593.3

101 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-[3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2- methylamino-propionamide593.3

102 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 592.3

103 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 592.3

104 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-[3-(1H-[1,2,3]triazol-4-yl)-phenyl]-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 578.2

105 (S)-N-{1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-2-[4-(3H-[1,2,3]triazol-4-yl)-phenyl]-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 578.2

106 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[3-(1H-[1,2,3]triazol-4-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 578.2

107 (S)-N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[4-(3H-[1,2,3]triazol-4-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide 578.2

108 3-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide597.3

1093-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide597.3

1103-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide582.3

1113-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl1-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide582.3

1123-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide 568.2

1133-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide 568.2

1143-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide583.3

1153-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide583.3

116 3-{5-((R)-3-Fluoro-2-methylamino-propionylamino)-1-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrimidin-2-yl}-N,N-dimethyl-benzamide 600.2

117 3-{5-((R)-3-Fluoro-2-methylamino-propionylamino)-1-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrazin-2-yl}-N,N-dimethyl-benzamide600.2

118 (R)-N-{2-(3-Cyano-phenyl)-1-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-3-fluoro-2-methylamino- propionamide 613.2

119 (R)-N-{5-(3-Cyano-phenyl)-4-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-3-fluoro-2-methylamino- propionamide 613.2

1203-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide581.3

1213-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide581.3

1223-[1-[3-Fluoro-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide599.3

1233-[1-[3-Fluoro-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide 599.3

124 3-[1-[3-Trifluoromethyl-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-l,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide649.3

125 3-[1-[3-Trifluoromethyl-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide649.3

126 3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide 650.3

127 3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]- N,N-dimethyl-benzamide650.3

1283-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide567.2

1293-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide567.2

1303-[1-[3-Fluoro-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide 585.2

1313-[1-[3-Fluoro-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide585.2

132 3-[1-[3-Trifluoromethyl-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2- yl]-N-methyl-benzamide635.2

133 3-[1-[3-Trifluoromethyl-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]- N-methyl-benzamide635.2

134 3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide636.3

135 3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide 636.3

136 3-[1-[3-(4-Fluoro-benzoyl)-5-trifluoromethyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl- benzamide 610.2

1373-[1-[3-(4-Fluoro-benzoyl)-5-trifluoromethyl-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide610.2

1383-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide611.3

1393-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide611.3

1403-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide582.3

1413-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide 582.3

1423-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide582.3

1433-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide 582.3

1443-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide597.3

1453-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide597.3

1463-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide597.3

1473-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide597.3

1483-[1-[3-(4-Fluoro-benzoyl)-5-isopropyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide598.3

1493-[1-[3-(4-Fluoro-benzoyl)-5-isopropyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide598.3

1503-[1-[3-(4-Fluoro-benzoyl)-5-isopropyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide597.3

1513-[1-[3-(4-Fluoro-benzoyl)-5-isopropyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide597.3

1523-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide581.3

1533-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide581.3

1543-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N,N-trimethyl-benzamide 595.3

1553-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N,N-trimethyl-benzamide595.3

1563-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide581.3

1573-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide581.3

1583-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N,N-trimethyl-benzamide 595.3

1593-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N,N-trimethyl-benzamide595.3

1603-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide 574.2

1613-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide 574.2

1623-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide 574.2

1633-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl)-4,N-dimethyl-benzamide 574.2

1643-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide 624.2

1653-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide624.2

1663-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide 624.2

1673-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide624.2

1683-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N,N-trimethyl- benzamide 638.2

1693-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N,N-trimethyl-benzamide 638.2

1703-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N,N-trimethyl-benzamide 638.2

1713-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N,N-trimethyl-benzamide 638.2

1723-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-2,N-dimethyl-benzamide 625.3

1733-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide625.3

1743-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-4,N-dimethyl-benzamide 625.3

1753-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide625.3

176 3-[1-[3-Trifluoromethyl-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N-methyl-benzamide623.6

177 3-[1-[3-Trifluoromethyl-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]- N-methyl-benzamide623.6

178 3-[1-[3-Trifluoromethyl-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-N,N-dimethyl-benzamide637.2

179 3-[1-[3-Trifluoromethyl-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide637.2

180 (S)-N-{1-[3-Fluoro-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-6-oxo-2-o-tolyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide 530.2

181(S)-N-{4-[3-Fluoro-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide530.2

182(S)-N-{1-[3-Fluoro-5-(4-fluoro-phenoxy)-benzyl]-6-oxo-2-o-tolyl-1,6-dihydro-pyrimidin-5-yl}-2-methylamino-propionamide505.2

183(S)-N-{-[4-[3-Fluoro-5-(4-fluoro-phenoxy)-benzyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide505.2

Biological Activity

TR-FRET is a proximity based detection method that requires a donorlabel, Europium (Eu-Streptavidin) and an acceptor label, APC(anti-GST-APC). In the absence of a competitive small molecule, theGST-BIR3 fusion protein binds specifically to its natural ligand Smac,or, in the context of this assay, to B-Smac (biotinylated Smac). Thesubsequent addition of donor and acceptor labeled complexes results inEuropium (via the Streptavidin:Biotin interaction) and APC (via theanti-GST:GST-BIR3 interaction) coming into proximity allowingfluorescence energy transfer. The excitation of Europium, by a 615 nMwavelength, results in the transfer of a singlet oxygen to the APCacceptor complex. This results in the excitation of APC and a release ofenergy detected at a wavelength of 665 nM. Compounds with Bir3 bindingactivity compete with Biotin-Smac for occupancy of the surface groove onGST-BIR3 resulting in concentration-dependent loss of signal. Assayplates are read on a multi-label plate reader using excitation andemission filters Europium 615 nM and APC 665 nM, respectively and theoptical module Lance Eu/APC Dual 452. The IC₅₀ (concentration ofcompound inhibiting 50% of Smac binding) is determined using XLfit4(IDBS) or Spotfire. Compounds 29-30 have IC₅₀ Range of 0.001-10 uM.

The above preferred embodiments are given to illustrate the scope andspirit of the present invention. The descriptions provided herein willmake apparent to those skilled in the art other embodiments andexamples. These other embodiments and examples are within thecontemplation of the present invention. Therefore, the present inventionshould be limited only by the appended claims.

1. A compound selected from the group consisting of(S)—N-(5-(4-Fluoro-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2-methylamino-propionamide;(S)—N-{5-(4-Fluoro-phenyl)-4-[2-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-amino)-acetyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{5-(4-Fluoro-phenyl)-4-[2-((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-amino)-ethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-[4-[(4-Fluoro-benzylcarbamoyl)-methyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-[4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N4-[5-(4-Fluoro-benzoyl)-pyridin-3-yl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-(5-(4-Fluoro-phenyl)-4-{5-[(4-fluoro-phenyl)-methyl-amino]-pyridin-3-ylmethyl}-3-oxo-3,4-dihydro-pyrazin-2-yl)-2-methylamino-propionamide;(S)—N-[4-[5-(5-Fluoro-2,3-dihydro-indol-1-yl)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-[4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-{5-(4-Fluoro-phenyl)-4-[1-(4-fluoro-phenyl)-1H-indol-4-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-[4-(5-Benzo[1,3]dioxol-5-yl-pyridin-3-ylmethyl)-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-4-[5-(4-Fluoro-phenoxy)-pyridin-3-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-{4-[4-(4-Fluoro-benzoyl)-thiazol-2-ylmethyl]-3-oxo-5-phenyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-[4-[4-(4-Fluoro-benzoyl)-thiazol-2-ylmethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)-2-Methylamino-N-(3-oxo-5-phenyl-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-propionamide;(S)—N-(5-(3-Trifluoromethyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{5-(4-Fluoro-phenyl)-4-[((R)-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl-carbamoyl)-methyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)-2-Methylamino-N-(3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-5-o-tolyl-3,4-dihydro-pyrazin-2-yl)-propionamide;(S)—N-(5-(4-Fluoro-2-methyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2-methylamino-propionamide;(S)—N-(5-(2,4-Dimethyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2-methylamino-propionamide;(S)—N-(5-(4-Fluoro-2-methyl-phenyl)-3-oxo-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-2-methylamino-butyramide;(S)—N-[4-[(1-Benzyl-2-phenyl-ethylcarbamoyl)-methyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N44-[(Diphenethylcarbamoyl)-methyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-[4-(2-Carbazol-9-yl-2-oxo-ethyl)-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-[4-[2-(1,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-5-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-{5-(4-Fluoro-phenyl)-4-[2-(indan-2-yloxy)-ethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{5-Benzo[1,3]dioxol-5-yl-4-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;3-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;(S)—N-{5-(3-Cyano-phenyl)-4-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{5-(3-Cyano-phenyl)-4-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;3-[1-[3-(4-Fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;N-Ethyl-3-[1-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-isobutyl-benzamide;(S)—N-{5-(3-Acetylamino-phenyl)-4-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;3-[1-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;(S)—N-[4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-5-(4-methoxy-pyridin-3-yl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-{5-Benzo[1,2,5]oxadiazol-5-yl-4-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{5-Benzo[1,2,5]oxadiazol-5-yl-4-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(4-Fluoro-benzoyl)-pyridin-3-ylmethyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;[3-((S)-2-Methylamino-propionylamino)-2-oxo-6-phenyl-2H-pyrazin-1-yl]-aceticacid 1,2,3,4-tetrahydro-naphthalen-1-yl ester;(S)—N-[4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-(2-pyrrolidin-1-yl-pyridin-4-yl)-3,4-dihydro-pyrazin-2-yl]-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-phenyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-phenyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[3-(2H-tetrazol-5-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[4-(1H-tetrazol-5-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-[3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[3-(1H-[1,2,3]triazol-4-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;(S)—N-{4-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-3-oxo-5-[4-(3H-[1,2,3]triazol-4-yl)-phenyl]-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;3-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;3-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;3-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-{5-((R)-3-Fluoro-2-methylamino-propionylamino)-1-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-6-oxo-1,6-dihydro-pyrazin-2-yl}-N,N-dimethyl-benzamide;(R)—N-{5-[3-Cyano-phenyl)-4-[3-(4-fluoro-benzoyl)-5-morpholin-4-yl-benzyl]-3-oxo-3,4-dihydro-pyrazin-2-yl}-3-fluoro-2-methylamino-propionamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;3-[1-[3-Fluoro-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;3-[1-[3-Trifluoromethyl-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[3-Fluoro-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[3-Trifluoromethyl-5-(5-fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-trifluoromethyl-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[5-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-3-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-ylmethyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-isopropyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-isopropyl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N,N-trimethyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[3-(5-Fluoro-3-methyl-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N,N-trimethyl-benzamide;3-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[3-Fluoro-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N,N-trimethyl-benzamide;3-[1-[3-Trifluoromethyl-5-(4-fluoro-benzoyl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N,N-trimethyl-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-2,N-dimethyl-benzamide;3-[1-[3-(4-Fluoro-benzoyl)-5-pyrrolidin-1-yl-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-4,N-dimethyl-benzamide;3-[1-[3-Trifluoromethyl-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N-methyl-benzamide;3-[1-[3-Trifluoromethyl-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-5-((S)-2-methylamino-propionylamino)-6-oxo-1,6-dihydro-pyrazin-2-yl]-N,N-dimethyl-benzamide;(S)—N-{4-[3-Fluoro-5-(5-fluoro-2,3-dihydro-indol-1-yl)-benzyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide;and(S)—N-{4-[3-Fluoro-5-(4-fluoro-phenoxy)-benzyl]-3-oxo-5-o-tolyl-3,4-dihydro-pyrazin-2-yl}-2-methylamino-propionamide.2. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 3. A compound which is(S)-2-Methylamino-N-(3-oxo-5-phenyl-4-{[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-methyl}-3,4-dihydro-pyrazin-2-yl)-propionamide,or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 3 and a pharmaceutically acceptable carrier.